Increased interaction of monocytes with endothelium appears to be among the earliest events in atherogenesis. This proposal is directed at a basic understanding of monocyte-EC interactions that initiate monocyte recruitment. Endothelial cells express several known adhesion molecules for monocytes; however, the currently characterized monocyte-endothelial cell adhesion pathways are not monocyte specific, and cannot per se explain the monocyte-selective adhesion observed in vivo. We have formulated two principal working hypothesis to direct our efforts to understand the mechanisms conferring physiologic specificity: 1) the first hypothesis posits the existence of as-yet-undefined truly monocyte-specific adhesion pathway(s) whose engagement is required for monocyte adhesion under physiologic settings. This hypothesis has already received some support since we have identified an apparently novel molecule expressed by stimulated endothelial cells that appears to be involved in monocyte adhesion. We propose to clone and characterize this novel adhesion molecule for monocytes. ?Although antibodies to this molecule inhibit monocyte binding to stimulated endothelial cells, substantial residual binding remains suggesting that additional adhesion pathways remain to be defined. Thus we also propose to produce and select additional blocking monoclonal antibodies against activated endothelial cells in order to identify and characterize additional novel adhesion molecules for monocytes. Further studies will be aimed at understanding the function and molecular characteristics of novel molecules defined. 2) The second hypothesis is that the specificity of monocyte adhesion is determined not by a single monocyte-specific adhesion pathway, but rather by an active, multi-step process of endothelial cell recognition in which specificity is determined by unique combinations known and/or novel adhesion molecules. This possibility will be addressed by immunocytochemical characterization of expression of novel elements identified as well as known adhesion elements on the endothelium of experimental or human early fatty streaks and atherosclerotic lesions. The molecular basis of the remarkable specificity of monocyte-endothelial interactions is of interest in understanding vascular differentiation, remodelling and inflammation-mediated vascular pathology in general.